Mechanical work and energetic analysis of eccentric cardiac remodeling in a volume overload heart failure in rats

Takewa, Yoshiaki; Chemaly, Elie R.; Takaki, Miyako; Li, Liang; Jin, Hongwei; Karakikes, Ioannis; Morel, Charlotte; Taenaka, Yoshiyuki; Tatsumi, Eisuke; Hajjar, Roger J.

doi:10.1152/ajpheart.01120.2008

Cited by 16 publications

(16 citation statements)

References 24 publications

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“…Allopurinol has also been shown to improve Ca 2ϩ homeostasis and oxidation/nitration of Ca 2ϩ -handling proteins in the tachypacing model in the dog (34) and in the spontaneously hypertensive rat (19). In the present study, there was no change in SERCA protein levels and that of its regulator, PLN, at 8 wk, whereas 12-wk ACF has been reported to have a decrease in SERCA2 expression associated with decreased LV contractility and the response to Ca 2ϩ infusion in the isolated ACF heart (13,36). It is of interest that we found an increase in SLN in ACF LVs that was decreased by allopurinol.…”

Section: Discussioncontrasting

confidence: 54%

Xanthine oxidase inhibition preserves left ventricular systolic but not diastolic function in cardiac volume overload

Gladden

Zelickson

Guichard

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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In the setting of increased ATP demand, XO-mediated ROS can decrease mitochondrial respiration and contractile function. Thus, we tested the hypothesis that XO inhibition improves cardiomyocyte bioenergetics and LV function in chronic ACF in the rat. Sprague-Dawley rats were randomized to either sham or ACF Ϯ allopurinol (100 mg·kg Ϫ1 ·day Ϫ1 , n Ն7 rats/group). Echocardiography at 8 wk demonstrated a similar 37% increase in LV end-diastolic dimension (P Ͻ 0.001), a twofold increase in LV end-diastolic pressure/wall stress (P Ͻ 0.05), and a twofold increase in lung weight (P Ͻ 0.05) in treated and untreated ACF groups versus the sham group. LV ejection fraction, velocity of circumferential shortening, maximal systolic elastance, and contractile efficiency were significantly depressed in ACF and significantly improved in ACF ϩ allopurinol rats, all of which occurred in the absence of changes in the maximum O 2 consumption rate measured in isolated cardiomyocytes using the extracellular flux analyzer. However, the improvement in contractile function is not paralleled by any attenuation in LV dilatation, LV end-diastolic pressure/wall stress, and lung weight. In conclusion, allopurinol improves LV contractile function and efficiency possibly by diminishing the known XO-mediated ROS effects on myofilament Ca 2ϩ sensitivity. However, LV remodeling and diastolic properties are not improved, which may explain the failure of XO inhibition to improve symptoms and hospitalizations in patients with severe heart failure. heart failure; volume overload; xanthine oxidase; mitochondria A PURE VOLUME OVERLOAD (VO), without an increase in systolic pressure, increases diastolic load and results in an adverse eccentric left ventricular (LV) hypertrophy and remodeling manifested by wall thinning, cardiomyocyte elongation, and a decrease in the LV mass to volume.Currently, there is no medical therapy to attenuate this remodeling process and progression to heart failure (10). Recently, our laboratory has demonstrated increased cardiomyocyte oxidative stress in patients with VO of isolated chronic mitral regurgitation (1) and in rats with VO of aortocaval fistula (ACF) (18, 39). Specifically, xanthine oxidase (XO) is elevated in cardiomyocytes along with myofibrillar degeneration and mitochondrial dysfunction and damage, despite a preserved LV ejection fraction (LVEF). The preservation of LV shortening has been shown to belie underlying cardiomyocyte dysfunction due to ejection into the low pressure left atrium and, in this animal model, ejection into the aortovenous fistula. XO is a critical mediator of ATP and purine degradation and produces ROS when O 2 is used as an electron acceptor during purine metabolism (30). We have postulated that increased myocardial O 2 demand in the volume-overloaded heart with increased XO activity and ATP turnover sets up a vicious cycle of ROS production that can negatively impact multiple processes in the cardiomyocyte by altering mitochondrial function and production of ROS that impact other sensiti...

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Section: Discussioncontrasting

confidence: 54%

Xanthine oxidase inhibition preserves left ventricular systolic but not diastolic function in cardiac volume overload

Gladden

Zelickson

Guichard

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…5D) -extrusion function of NCX1 is facilitated in the present hypertrophied hearts, the O 2 cost of LV contractility might have increased (14,31). A recent study reported that PLM regulates cardiac contractility by modulating NKA and/or NCX1, although at present the mechanism by which PLM regulates cardiac contractility is being actively investigated and is a topic of lively debated (23).…”

Section: Discussionmentioning

confidence: 78%

“…1 in Table 3) to an experimentally obtained series of five to six paired LV P-V data to obtain a set of ESPVR and EDPVR. Thus we determined PVA by subtracting the area under the best-fit EDPVR from the area under the best-fit ESPVR (1,19,31). In the present study, we calculated PVA at mLVV (PVA mLVV) to assess LV mechanical work based on our studies (1,6,19,32,33).…”

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confidence: 99%

Left ventricular function of isoproterenol-induced hypertrophied rat hearts perfused with blood: mechanical work and energetics

Nakajima-Takenaka

Zhang

Okihara

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Ϫ1 ⅐ day Ϫ1 for 3 days (Iso3) or 7 days (Iso7)]-induced hypertrophied rat heart preparation under isovolumic contractionrelaxation. We evaluated pressure-time curves per beat, end-systolic pressure-volume and end-diastolic pressure-volume relations, and myocardial O 2 consumption per beat (V O2)-systolic pressure-volume area (PVA; a total mechanical energy per beat) linear relations at 240 beats/min, because Iso-induced hypertrophied hearts failed to completely relax at 300 beats/min. The LV relaxation rate at 240 beats/min in Iso-induced hypertrophied hearts was significantly slower than that in control hearts [saline 24 l/day for 3 and 7 days (Sa)] with unchanged contraction rate. The V O2-intercepts (composed of basal metabolism and Ca 2ϩ cycling energy consumption in excitationcontraction coupling) of V O2-PVA linear relations were unchanged associated with their unchanged slopes in Sa, Iso3, and Iso7 groups. The oxygen costs of LV contractility were also unchanged in all three groups. The amounts of expression of sarcoplasmic reticulum Ca 2ϩ -ATPase, phospholamban (PLB), phosphorylated-Ser 16 PLB, phospholemman, and Na ϩ -K ϩ -ATPase are significantly decreased in Iso3 and Iso7 groups, although the amount of expression of NCX1 is unchanged in all three groups. Furthermore, the marked collagen production (types I and III) was observed in Iso3 and Iso7 groups. These results suggested the possibility that lowering the heart rate was beneficial to improve mechanical work and energetics in isoproterenol-induced hypertrophied rat hearts, although LV relaxation rate was slower than in normal hearts. cardiac function; excitation-contraction coupling; systolic pressurevolume area; oxygen consumption CARDIAC HYPERTROPHY IS A MAJOR risk factor for the development of heart failure and sudden cardiac death. Therefore, to reduce mortality from cardiovascular diseases, elucidation of the mechanisms involved in cardiac hypertrophy is pivotal. It is recognized that activation of the sympathetic nervous system is associated with cardiac hypertrophy and heart failure in humans (4, 11). In addition, chronic treatment of hearts with an ␣,␤-stimulant, norepinephrine, or a ␤-stimulant, isoproterenol, induces cardiac hypertrophy accompanied with enhanced fibrosis among cardiac interstitial cells in experimental animal models (3,21,25,26). So far, various mechanisms for this remodeling have been proposed (25,26,10,36).We have recently reported that 3-day and 7-day subcutaneous infusions of isoproterenol to rats induced cardiac hypertrophy with unchanged left ventricular (LV) systolic and diastolic functions compared with normal hearts that was reversible to the control levels after the cessation of infusion (8,30). In in vivo ejecting heart model, the significant decrease of mechanical work due to the decrease of LV volume (LVV) was observed. Furthermore, these short-term models did not show any marked differences in the LV mechanical work capability compared with that induced by a 2-wk isoproterenol infusion (30). The expression l...

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“…The rat model of chronic HF due to volume overload induced by aorto-caval fistula has been previously well characterized [17][18][19]. It shares many similarities with the natural course of human HF including gradual development of the disease that proceeds through a stage of compensated hypertrophy followed by gradual decompensation into the overt HF [19], neurohumoral activation, cardiac output redistribution [20], fluid retention with pulmonary congestion and impairment of myocardial efficiency [21]. On the other hand, volume overload-induced HF has several features distinct from other HF models including a lack of myocardial fibrosis and inflammation [22,23] and involvement of different signalling pathways (upregulation of Akt and Wnt signalling) compared to experimental myocardial infarction or pressure overload [23].…”

Section: Introductionmentioning

confidence: 99%

Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats

et al. 2011

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The effect of metformin therapy on cardiac function and survival in volume-overload model of heart failure in rats Short title: Metformin therapy in volume-overload heart failure in rats A c c e p t e d M a n u s c r i p t Licenced copy. Copying is not permitted, except with prior permission and as allowed by law.© 2011 The Authors Journal compilation © 2011 Portland Press Limited 2 Abstract Aims: Advanced heart failure (HF) is associated with altered substrate metabolism. Whether modification of substrate use improves the course of HF remains unknown. Antihyperglycemic drug metformin (MET) affects substrate metabolism and its use might be associated with improved outcome in diabetic HF. The aim of the study was to examine whether MET would improve cardiac function and survival also in non-diabetic HF. Methods: Volume overload HF was induced in male Wistar rats by creating aorto-caval fistula (ACF). Animals were randomized to placebo/MET (300mg/kg/day, 0.5% in food) groups and underwent assessment of metabolism, cardiovascular and mitochondrial functions (n=6-12/group) in advanced HF stage (21 st week). A separate cohort served for survival analysis (n=10-90/group). Results: The ACF group had marked cardiac hypertrophy, increased LVEDP and lung weight confirming decompensated HF, increased circulating free fatty acids (FFA), intraabdominal fat depletion, lower glycogen synthesis in the skeletal muscle (diaphragm), lower myocardial triglyceride content and attenuated myocardial 14 C-glucose and 14 C-palmitate oxidation, but preserved mitochondrial respiratory function, glucose tolerance and insulin sensitivity. MET therapy normalized serum FFA, decreased myocardial glucose oxidation, increased myocardial palmitate oxidation, but it had no effect on myocardial gene expression, AMPK signalling, ATP level, mitochondrial respiration, cardiac morphology, function and long-term survival despite reaching therapeutic serum level (2.2 ± 0.7 μg/ml). Conclusion: MET-induced enhancement of myocardial fatty acid oxidation had neutral effect on cardiac function and survival. Recently reported cardioprotective effects of MET may not be universal to all forms of HF and may require AMPK activation or ATP depletion. No increase in mortality on MET supports its safe use in diabetic HF. IntroductionAdvanced heart failure (HF) is characterized not only by a depression of heart mechanical performance but also by altered myocardial metabolism -attenuated expression of fatty acid oxidation genes [1,2] and by diminished oxidation of long chain fatty acids [1,[3][4][5], which may contribute to diminished metabolic flexibility and to energetic deficiency that further promotes worsening of HF [6]. Targeting energetic substrate metabolism might thus serve as a target for novel therapeutic approaches to HF [7,8]. Metformin (MET), a widely used antihyperglycemic drug with insulin-sensitizing properties, could be a suitable candidate for metabolic HF therapy. MET lowers serum glucose by inhibiting liver gluconeogenesis, lowers circulating free...

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Mechanical work and energetic analysis of eccentric cardiac remodeling in a volume overload heart failure in rats

Cited by 16 publications

References 24 publications

Xanthine oxidase inhibition preserves left ventricular systolic but not diastolic function in cardiac volume overload

Xanthine oxidase inhibition preserves left ventricular systolic but not diastolic function in cardiac volume overload

Left ventricular function of isoproterenol-induced hypertrophied rat hearts perfused with blood: mechanical work and energetics

Effect of metformin therapy on cardiac function and survival in a volume-overload model of heart failure in rats

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